Deafness and renal tubular acidosis in mice lacking the K-Cl co-transporter Kcc4

Boettger, Thomas; Hübner, Christian A.; Maier, Hannes; Rust, Marco B.; Beck, Franz‐Xaver; Jentsch, Thomas J.

doi:10.1038/416874a

Cited by 361 publications

(318 citation statements)

References 29 publications

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“…Siphoning is mediated by electro-neutral K/Cl co-transporters (Boettger et al 2002;Boettger et al 2003). This transport may be kept energetically favorable by a constant clearance of K + from the Deiters' cell cytoplasm, via an intercellular gap junctional pathway (Jagger and Forge 2006).…”

Section: Root Cells Form the Lateral Limits Of The Epithelial Gap Junmentioning

confidence: 99%

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The Membrane Properties of Cochlear Root Cells are Consistent with Roles in Potassium Recirculation and Spatial Buffering

Jagger

Nevill

Forge

2010

JARO

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Auditory transduction, amplification, and hair cell survival depend on the regulation of extracellular [K + ] in the cochlea. K + is removed from the vicinity of sensory hair cells by epithelial cells, and may be distributed through the epithelial cell syncytium, reminiscent of "spatial buffering" in glia. Hypothetically, K + is then transferred from the epithelial syncytium into the connective tissue syncytium within the cochlear lateral wall, enabling recirculation of K + back into endolymph. This may involve secretion of K + from epithelial root cells, and its re-uptake via transporters into spiral ligament fibrocytes. The molecular basis of this secretion is not known. Using a combination of approaches we demonstrated that the resting conductance in guinea pig root cells was dominated by K + channels, most likely composed of the Kir4.1 subunit. Dye injections revealed extensive intercellular gap junctional coupling, and delineated the root cell processes that penetrated the spiral ligament. Following uncoupling using 1-octanol, individual cells had Ba 2+ -sensitive weakly rectifying currents. In the basal (high-frequency encoding) cochlear region K + loads are predicted to be the highest, and root cells in this region had the largest surface area and the highest current density, consistent with their role in K + secretion. Kir4.1 was localized within root cells by immunofluorescence, and specifically to root cell process membranes by immunogold labeling. These results support a role for root cells in cochlear K + regulation, and suggest that channels composed of Kir4.1 subunits may mediate K + secretion from the epithelial gap junction network.

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Section: Root Cells Form the Lateral Limits Of The Epithelial Gap Junmentioning

confidence: 99%

“…Accumulation of K + in the vicinity of hair cells is prevented by transporters expressed by underlying epithelial supporting cells (Boettger et al 2002;Boettger et al 2003;Hibino and Kurachi 2006). Supporting cells are contained within the epithelial gap junction network (Fig.…”

Section: Introductionmentioning

confidence: 99%

The Membrane Properties of Cochlear Root Cells are Consistent with Roles in Potassium Recirculation and Spatial Buffering

Jagger

Nevill

Forge

2010

JARO

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“…However, prolonged IHC survival after extensive OHC loss has been observed in mice with specific genetic alterations that lead to HC death. In mice lacking the Kcc4 cotransporter, IHCs can survive for several months (Boettger et al 2002), and IHCs can be present at 6 months in Barhl1-deficient mice while the OHCs are completely lost by postnatal day 59 (Li et al 2002).…”

Section: Increased Ihc Loss With Timementioning

confidence: 99%

Supporting Cell Characteristics in Long-deafened Aged Mouse Ears

Oesterle

Campbell

2009

JARO

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Significant sensory hair cell loss leads to irreversible hearing and balance deficits in humans and other mammals. Future therapeutic strategies to repair damaged mammalian auditory epithelium may involve inserting stem cells into the damaged epithelium, inducing non-sensory cells remaining in the epithelium to transdifferentiate into replacement hair cells via gene therapy, or applying growth factors. Little is currently known regarding the status and characteristics of the non-sensory cells that remain in the deafened auditory epithelium, yet this information is integral to the development of therapeutic treatments. A single high-dose injection of the aminoglycoside kanamycin coupled with a single injection of the loop diuretic furosemide was used to kill hair cells in adult mice, and the mice were examined 1 year after the drug insult. Outer hair cells are lost throughout the entire length of the cochlea and less than a third of the inner hair cells remain in the apical turn. Over 20% and 55% of apical organ of Corti support cells and spiral ganglion cells are lost, respectively. We examined the expression of several known support cell markers to investigate for possible support cell dedifferentiation in the damaged ears. The support cell markers investigated included the microtubule protein acetylated tubulin, the transcription factor Sox2, and the Notch signaling ligand Jagged1. Non-sensory epithelial cells remaining in the organ of Corti retain acetylated tubulin, Sox2 and Jagged1 expression, even when the epithelium has a monolayer-like appearance. These results suggest a lack of marked SC dedifferentiation in these aged and badly damaged ears.

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“…However, no animal models for this gene are yet available (Kubisch et al 1999). More recently, a K-Cl cotransporter, Kcc4, that is expressed in the Deiters' and phalangeal cells has been postulated to participate in the recycling of potassium ions that have exited hair cells into supporting cells (Boettger et al 2002). Mice lacking Kcc4 function are deaf and display renal tubular acidosis.…”

Section: Genes That Affect Fluid Homeostasismentioning

confidence: 99%